Suppository vehicle and process of making same

ABSTRACT

The suppository vehicle material of this invention consists of hard fat, the hydroxyl number of which has been reduced to less than 10 and preferably to less than 3, by esterification of the free hydroxyl groups of said hard fat with mono-alkanoic acids with one to eight carbon atoms. Such suppository vehicle material is especially suitable for preparing suppositories with drugs having acid groups, such as acetyl salicylic acid. The resulting suppositories are stable even on prolonged storage and at deep freeze temperatures, do not become brittle, have a sharp melting point, and solidify rapidly and completely in suppository molds.

Neissner et al.

[ Sept. 5, 1972 SUPPOSITORY VEHICLE AND PROCESS OF MAKING SAME Inventors: Rudolf Neissuer, Hamburg-Meiendorf; Eckhard Schulz, Halstenbek, rdfiamw gabeth 9!.-.Q1m ny Edeliettwerke Werner Schlueter, Hamburg 57, Germany Filed: May 21, 1969 Appl. No.2 826,677

Assignee:

US. Cl. ..260/4l0.8, 260/410.7, 128/271 Int. Cl ..Cl 1c 3/08, A6lk 9/06 Field of Search ..260/410.8, 4107 References Cited UNITED STATES PATENTS 10/1952 Baur et al. ..99/118 10/1952 Jackson ..260/410.8 10/1952 Baur ..260/4l0.8 10/1957 Brokaw ..260/4 1 0.8

FOREIGN PATENTS OR APPLICATIONS 822,730 10/1959 Great Britain ..260/410.8

Primary ExaminerLewis Gotts Assistant Examiner-Diana G. Rivers Att0rneyErich M. Radde, Charles A. McClure, Gerard J. Weiser and Alfred Stapler [57] ABSTRACT The suppository vehicle material of this invention consists of hard fat, the hydroxyl number of which has been reduced to less than 10 and preferably to less than 3, by esterification of the free hydroxyl groups of said hard fat with mono-alkanoic acids with one to eight carbon atoms. Such suppository vehicle material is especially suitable for preparing suppositories with drugs having acid groups, such as acetyl salicylic acid. The resulting suppositories are stable even on pro-' longed storage and at deep freeze temperatures, do not become brittle, have a sharp melting point, and solidify rapidly and completely in suppository molds.

6 Claims, No Drawings SUPPOSITORY VEHICLE AND PROCESS OF MAKING SAME BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to suppositories and more particularly to suppository vehicle material well compatible with all kind of drugs and to a process of making and using same.

2. Description of the Prior Art Suppository vehicle materials must meet various requirements. For instance, they must have a sharp melting point within narrow limits of temperature and without passing through an appreciable softening stage. They must rapidly and completely solidify on molding in the suppository molds without requiring pretreatment of the molds. Their melting point must be readily and exactly adjustable.

Cocoa butter or theobroma oil which has been used heretofore for this purpose exhibits polymorphism and forms an unstable modification on melting and solidifying. Therefore, it has frequently been replaced by solid or hard fat as it is prepared, for instance, according to German Pat. No. 941,014; see also US. Pat. No. 2,182,332. Such hard fats are essentially mixtures of esters of fatty acids with 12 to 20 carbon atoms with polyvalent alcohols, preferably glycerol. Such suppository vehicle materials have usually a hydroxyl number of about 10 to about 65. Due to the presence of free hydroxyl groups said vehicles are capable of reacting with certain drugs and more particularly with drugs which contain acid groups such as, for instance, acetyl salicylic acid. To prepare suppositories with such acid drugs requires suppository vehicle materials with as low a hydroxyl number as possible. However, when trying to reduce the hydroxyl number to less than 10 by esterifying the fatty acids with polyvalent alcohols, brittle hard fats which are unsuitable for molding suppositories are obtained.

SUMMARY OF THE INVENTION It is one object of the present invention to provide suppository vehicle materials consisting of hard fats which have a hydroxyl number lower than 10 and preferably a hydroxyl number of about but which are not, and do not become, brittle and which possess all the other valuable properties of hard fat suppositories, such as a readily adjustable melting point, great stability, and storability, remarkable ability of maintaining its firmness, compatibility even with acid drugs, and which can readily be processed to rolled or hand-made, molded, and machine-made or pressed suppositories.

Another object of the present invention is to provide a simple and effective process of making such valuable suppository vehicle materials.

A further object of the present invention is to provide suppositories of such a hard fat vehicle material with a low hydroxyl number.

Other objects and advantageous features of the present invention will become apparent as the description In principle, the hard fat suppository vehicle material according to the present invention is produced by substantially completely esterifying the free hydroxyl groups of the hard fat with low molecular monobasic carboxylic acids having one to eight carbon atoms in their molecule in such a manner that the resulting substantially completely esterified hard fat does not become brittle. This is achieved by special selection of acid groups in the second esterification step. The acetyl group has been found to be a very good plastifier.

The esterifying process according to the present invention is carried out by reacting the starting suppository fats having a higher hydroxyl number with esterifying derivatives of low molecular carboxylic acids, preferably with the anhydrides or the acid halides of said acids. The resulting suppository fats have a hydroxyl number of about 0. They do not react with reactive drugs and do not exhibit other disadvantages either on using the same.

Esterification may also be effected by reaction with the concentrated monocarboxylic acids, for instance, with glacial acetic acid. This reaction usually requires the presence of suitable catalysts such as concentrated sulfuric acid, organic sulfonic acids, aluminum chloride, or the like.

Usually, esterification is effected at elevated temperature, whereby the esterification mixture is heated to a temperature below the boiling point of the reactants. Working under superatmospheric pressure is not necessary. However, when working near the boiling point of the esterifying agent, a reflux condenser is preferably used. Such a reflux condenser may also be used when esterification is carried out in the presence of an organic solvent. It is understood, of course, that usually such a solvent is not required. Esterification is ordinarily completed within several hours when operating at a temperature below C. At 100 C. and above, esterification is completed within about 30 minutes. In general the esterification time varies between 20 minutes and 4 to 8 hours.

It is advisable to substantially completely exclude water during esterification in order to facilitate the reaction. When esterifying under reflux, the reflux condenser is preferably provided with a calcium chloride tube or similar drying means so as to exclude access of moisture to the reaction mixture.

The gases or vapors generated during the reaction are preferably removed by suction so as not to annoy or trouble the surroundings.

The resulting suppository vehicle material does not differ in its appearance, properties, and technical usefulness from the known hard fat material. It is not brittle and does not crack on melting and solidifying. Furthermore, it has the valuable property that the reactivity of the initially present hydroxyl groups is substantially completely eliminated. As a result thereof, suppositories made with such a vehicle have a substantially unlimited stability and shelf-life even when highly reactive drugs are incorporated thereinto.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples serve to illustrate the present invention without, however, being limited thereto.

EXAMPLE 1 200 g. of hard fat, i.e. a mixture of esters of glycerol with saturated fatty acids having 12 to 20 carbon atoms in their molecule, said mixture having a melting point of 34.8 C. and a hydroxyl number of 15, are heated to 100 C. with 15 g. of acetylchloride for 90 minutes while stirring. Thereafter, excess acetylchloride is decomposed by treating the reaction mixture with water, the resulting esterified hard fat is freed of acetic acid by washing with warm water, refined by a treatment with warm aqueous percent sodium hydroxide solution, allowed to settle, freed of any soap formed by washing with warm water, dried at 90 C. in a vacuum of mm. Hg, and filtered. The resulting suppository vehicle material has a melting point of 349 C. and a hydroxyl number of 0.

EXAMPLE 2 200 g. of hard fat of a melting point of 34.8 C. and a hydroxyl number of 20 is heated with 18 g. of propionyl bromide at 100 C. for 90 minutes while stirring. Excess propionyl bromide is decomposed by treating the reaction mixture with warm water. The resulting esterified hard fat is washed with warm water until it is free of propionic acid, refined as described in Example 1, dried, and filtered. The resulting suppository vehicle material has a melting point of 35.0 C. and a hydroxyl number of 1.

EXAMPLE 3 200 g. of hard fat of a melting point of 34.5 C. and a hydroxyl number of 25 are heated at 100 C. with 30 g. of hexanoic acid anhydride for 4 hours while stirring. Excess hexanoic acid anhydride is decomposed by treating the reaction mixture with warm water. The reaction product is then repeatedly washed with warm aqueous 1 percent sodium hydroxide solution to remove any remaining free acid. The washed esterified hard fat is refined as described in Example 1, dried, and filtered. The resulting suppository vehicle material has a melting point of 34.9 C. and a hydroxyl number of 1 EXAMPLE 4 200 g. of hard fat of a melting point of 345C. and a hydroxyl number 17 are heated at 100 C. with 25 g. of butyric acid anhydride for 4 hours while stirring. Excess butyric acid anhydride is decomposed by treating the reaction mixture with warm water. The esterification product is then de-acidified by repeated washing with warm aqueous 1 percent sodium hydroxide solution. The washed esterified hard fat is refined as described in Example 1, dried, and filtered. The resulting suppository vehicle material has a melting point of 349 C. and a hydroxyl number of 1.8.

EXAMPLE 5 200 g. of hard fat of a melting point of 345C. and a hydroxyl number of 17 is heated at 100 C. with 25 g. of valeric acid anhydride for 4 hours while stirring. Excess valeric acid anhydride is decomposed by treating the reaction mixture with warm water. The esterification product is then de-acidified by repeated washing with warm aqueous 1 percent sodium hydroxide solution. The washed esterified hard fat is refined as described in Example 1, dried, and filtered. The resulting suppository vehicle material has a melting point of 34.8 C. and a hydroxyl number of 2.6.

EXAMPLE 6 200 g. of hard fat of a melting point of 34.8C and a hydroxyl number of 17 is heated under reflux at about 115 C. with 42 g. of percent formic acid for 6 hours while stirring. The major portion of excess formic acid is removed by heating in a vacuum of 20 mm. Hg. The reaction mixture is then repeatedly washed with warm water to de-acidify the same. The acid-free esterified hardfat is refined as described in Example 1, dried, and filtered. The resulting suppository vehicle material has a melting point of 35.1 C. and a hydroxyl number of 3. 7

Of course, in place of the monocarboxylic acids and their reactive derivatives used in the preceding exam ples, there may be employed other monocarboxylic acids and their derivatives such as heptanoic acid, octanoic acid, and the like, and their derivatives while the reaction is carried out in essentially the same manner as described in said examples. Mixtures of such acids or their derivatives may also be used.

The preferred hard fat used as starting material is the adeps solidus of the German Pharmacopoea (Deutsches Arzneibuch 7), pages 552 and 553. It is a mixture of mono-, di-, and triglycerides of the saturated fatty acids C I-1 0 to C I-I O It is a white, friable, almost tasteless and odorless material of a greasy feel which melts, on heating, to a colorless to slightly yellowish liquid. It is readily soluble in ether and benzene, difficultly soluble in absolute ethanol, and practically insoluble in water. Its melting point is between about 335 and 35.5 C. Its acid number is not higher than 0.3, its iodine number is not higher than 7.0, and its non-saponifiable components do not exceed 0.3 percent. Its saponification number is between 225 and 240, and its hydroxyl number between 10 and 50. Its residue on combustion is at the most 0.05 percent. The hard fat does not have a rancid smell and taste. Its peroxide number is not higher than 6.0.

Of course, other types of hard fat of similar constitution and properties may also be used provided they yield, on esterification with aliphatic monocarboxylic acids with one to eight carbon atoms, a completely esterified hard fat of a melting point between 335 and 35 .5 C. and preferably between 34.0 and 350 C.

The preferred esters are the mixtures of mono-, di-, and triglycerides of fatty acids known as hard fat, i.e. adeps solidus. Thus the term hard fat as used in the specification and claims annexed hereto refers to any type of esters of fatty acids having 12 to 20 carbon atoms in their molecule, with polyvalent alcohols and especially with glycerol, which have a melting point between 33.5 and 355 C. and a hydroxyl number between 10 and 50.

Suppositories are prepared in a manner known per se, for instance, by melting the substantially completely esterified hard fat according to the present invention, dissolving or finely distributing in said melt the desired drugs, and molding the molten mixture into suppository molds. The resulting suppositories are stable and storable for a prolonged period of time and do not become brittle, even on deep freezing. They are compatible with all types of drugs and especially with drugs having acid groups such as acetyl salicylic acid.

The following comparative tests were carried out with suppositories containing the following drugs:

Aceto phenetidine 0.20 g. Acetyl salicylic acid 0.25 g. Caffeine 0.10 g. Suppository vehicle ad 2.00 g.

TABLE Free salicylic acid content Hard fat Esterified hard fat lmmediately after suppository preparation 0.6 0.3 Three months thereafter 1.0 0.3 Six months thereafter 2.0 0.3

According to the regulations of the Food and Drug Administration the free salicylic acid content of such suppositories should not exceed 0.8 percent. Therefore, as is evident from the above given data, the heretofore used hard fat suppositories cannot be stored for a prolonged period of time. In contrast thereto the suppositories made with substantially completely esterified hard fat according to the present invention can be stored for six months and longer without any appreciable increase in free salicylic acid content.

The reason for the increase in free salicylic acid content, when using the conventional hard fat as suppository vehicle, is that the acetyl salicylic acid reacts with the free hydroxyl groups of the hard fat, whereby re-arrangement of the acetyl groups and their transfer from the acetyl salicylic acid to the hard fat takes place. As a result thereof the normal equilibrium acetyl salicylic acid/salicylic acid/acetyl groups is shifted in accordance with the Law of Mass Action towards the salicylic acid. No such re-arrangement and shifting of the equilibrium takes place, and can take place, when using the substantially completely esterified hard fat according to the present invention.

Of course, other drugs than those mentioned hereinabove may be incorporated into the suppository vehicle material according to the present invention.

Such suppository vehicle material according to the present invention has proved to be especially useful, for instance, for rectal administration of the following drugs, although it is not limited thereto:

Amino acridine hydrochloride, aminophylline, boric acid, benzoic acid, bismuthum carbonate, bismuthum salicylate, bismuthum subgallate, carbarsone, chloral hydrate, chrysarobin, cocaine hydrochloride, dihydromorphinone, glycerol, iodoforrn, lead acetate, menthol, morphine hydrochloride, Peruvian balsam, phenol, phenyl salicylate, protein silver, phenobarbital, procaine, quinine hydrochloride, resorcinol, salol, sulfanilamides, sulfur, tannic acid, zinc oleate, zinc oxide, and others.

The suppositories may be prepared in a manner known per se, such as by rolling by hand or by pouring the molten mixture or solution of suppository vehicle according to the present inventlon and of the drug into a chilled mold, or by machine molding or pressing. Of course, not only rectal suppositories but also more or less globular vaginal suppositories, or pencil shaped urethral suppositories or bougies may be prepared with such vehicle.

We claim:

1. Suppository vehicle material obtained by esterifying a hard fat of a hydroxyl number between about 10 and about 50 and a melting point between about 33.5 and 355C. with a mono-alkanoic acid with one to eight carbon atoms, said suppository vehicle material having a hydroxyl number not exceeding about 3 and a sharp melting point between 335 and 355C. without passing through an appreciable softening stage, being stable on prolonged storage, not becoming brittle even on deep freezing, and, after melting, solidifying rapidly and completely without cracking.

2. Suppository vehicle material according to claim I, wherein the hard fat is a mixture of mono-, di-, and triglycerides of fatty acids with 12 to 18 carbon atoms.

3. Suppository vehicle material according to claim 1, wherein the esterified hard fat has a hydroxyl number of about zero.

4. Suppository vehicle material according to claim 1, wherein the melting point of the esterified hard fat is between 34.0 and 35.0C.

5. Suppository vehicle material according to claim 1, wherein the mono-alkanoic acid is acetic acid.

6. Suppository vehicle material according to claim 1, wherein the mono-alkanoic acid is propionic acid. 

2. Suppository vehicle material according to claim 1, wherein the hard fat is a mixture of mono-, di-, and triglycerides of fatty acids with 12 to 18 carbon atoms.
 3. Suppository vehicle material according to claim 1, wherein the esterified hard fat has a hydroxyl number of about zero.
 4. Suppository vehicle material according to claim 1, wherein the melting point of the esterified hard fat is between 34.0* and 35.0* C.
 5. Suppository vehicle material according to claim 1, wherein the mono-alkanoic acid is acetic acid.
 6. Suppository vehicle material according to claim 1, wherein the mono-alkanoic acid is propionic acid. 